Despite the effectiveness of triple drug combinations in anti-HIV chemotherapy, there are still several critical issues remaining to be resolved in HIV chemotherapy. The first issue is the viral reservoir. Triple combination therapy (two nucleoside reverse transcriptase inhibitors plus one protease inhibitor) can virtually eliminate the HIV viral load to undetectable level in the serum in many HIV patients who are undergoing therapy. There are at least two other major compartments which should be considered: the central nervous and the lymphatic system. In this application, Dr. Chu will continue to study these two systems with some proposed prodrugs to improve their pharmacokinetics/ pharmacodynamic profiles. If any prodrugs are found to be promising during these studies, the focus will be on them to determine their potential as clinical candidates. Studies will include pharmacokinetic/pharmacodynamic studies in mice, rats and rhesus monkeys. In view of the number of children born with HIV infection, another area of focus is the maternal-fetal drug delivery issue which will be investigated using a rat model. Additionally, as drug interactions have become an increasingly important issue in HIV chemotherapy this will also be studied in vitro and in animal models to provide information on cellular, virological, pharmacological and toxicological interactions.